URINARY TRACT INFECTION
among men as among women. Between 1 year and ~50
Urinary tract infection (UTI) is a common and painful
human illness that, fortunately, is rapidly responsive to
modern antibiotic therapy. In the preantibiotic era, UTI
caused significant morbidity. Hippocrates, writing about a
disease that appears to have been acute cystitis, said that the
illness could last for a year before either resolving or
worsening to involve the kidneys. When chemotherapeutic
agents used to treat UTI were introduced in the early
twentieth century, they were relatively ineffective, and
persistence of infection after 3 weeks of therapy was
common. Nitrofurantoin, which became available in the
1950s, was the first tolerable and effective agent for the
treatment of UTI. Since the most common manifestation of
UTI is acute cystitis and since acute cystitis is far more
prevalent among women than among men, most clinical
research on UTI has involved women. Many studies have
enrolled women from college campuses or large health
maintenance organizations in the United States. Therefore,
when reviewing the literature and recommendations
concerning UTI, clinicians must consider whether the
findings are applicable to their patient populations.
DEFINITIONS
UTI may be asymptomatic (subclinical infection) or
symptomatic (disease). Thus, the term urinary tract
infection encompasses a variety of clinical entities,
including asymptomatic bacteriuria (ASB), cystitis,
prostatitis, and pyelonephritis. The distinction between
symptomatic UTI and ASB has major clinical implications.
Both UTI and ASB connote the presence of bacteria in the
urinary tract, usually accompanied by white blood cells and
inflammatory cytokines in the urine.
However, ASB occurs in the absence of symptoms
attributable to the bacteria in the urinary tract and usually
does not require treatment, while UTI has more typically
been assumed to imply symptomatic disease that warrants
antimicrobial therapy. Much of the literature concerning
UTI, particularly catheter-associated infection, does not dif-
ferentiate between UTI and ASB. In this chapter, the term
urinary tract infection denotes symptomatic disease;
cystitis, symptomatic infection of the bladder; and
pyelonephritis, symptomatic infection of the kidneys.
Uncomplicated urinary tract infection refers to acute
cystitis or pyelonephritis in nonpregnant outpatient women
without anatomic abnormalities or instrumentation of the
urinary tract; the term complicated urinary tract infection
encompasses all other types of UTI. Recurrent urinary
tract infection is not necessarily complicated; individual
episodes can be uncomplicated and treated as such.
Catheter-associated bacteriuria can be either symptomatic
(CAUTI) or asymptomatic.
EPIDEMIOLOGY AND RISK FACTORS
Except among infants and the elderly, UTI occurs far more
commonly in females than in males. During the neonatal
period, the incidence of UTI is slightly higher among males
than among females because male infants more commonly
have congenital urinary tract anomalies. After 50 years of
age, obstruction from prostatic hypertrophy becomes com-
mon in men, and the incidence of UTI is almost as high
years of age, UTI and recurrent UTI are predominantly
diseases of females. The prevalence of ASB is ~5% among
women between ages 20 and 40 and may be as high as 40–
50% among elderly women and men.
As many as 50–80% of women in the general population
acquire at least one UTI during their lifetime—
uncomplicated cystitis in most cases. Recent use of a
diaphragm with spermicide, frequent sexual intercourse,
and a history of UTI are independent risk factors for acute
cystitis. Cystitis is temporally related to recent sexual
intercourse in a dose–response manner, with an increased
relative risk ranging from 1.4 with one episode of
intercourse in the preceding week to 4.8 with five episodes.
In healthy postmenopausal women, sexual activity, diabetes
mellitus, and incontinence are risk factors for UTI.
Many factors predisposing women to cystitis also
increase the risk of pyelonephritis. Factors independently
associated with pyelonephritis in young healthy women
include frequent sexual intercourse, a new sexual partner, a
UTI in the previous 12 months, a maternal history of UTI,
diabetes, and incontinence. The shared risk factors for
cystitis and pyelonephritis are not surprising given that
pyelonephritis typically arises through the ascent of
bacteria from the bladder to the upper urinary tract.
However, pyelonephritis can occur without symptomatic
antecedent cystitis.
About 20–30% of women who have had one episode of
UTI will have recurrent episodes. Early recurrence (within
2 weeks) is usually regarded as relapse rather than
reinfection and may indicate the need to evaluate the
patient for a sequestered focus. Intracellular pods of
infecting organisms within the bladder epithelium have
been demonstrated in animal models of UTI, but the
clinical impact of this phenomenon in humans is not yet
clear. The rate of recurrence ranges from 0.3 to 7.6
infections per patient per year, with an average of 2.6
infections per year. It is not uncommon for multiple
recurrences to follow an initial infection, resulting in
clustering of episodes. Clustering may be related
temporally to the presence of a new risk factor, to the
sloughing of the protective outer bladder epithelial layer in
response to bacterial attachment during acute cystitis, or
possibly to antibiotic-related alteration of the normal flora.
The likelihood of a recurrence decreases with increasing
time since the last infection. A case–control study of
predominantly white premenopausal women with recurrent
UTI identified frequent sexual intercourse, use of
spermicide, a new sexual partner, a first UTI before 15
years of age, and a maternal history of UTI as independent
risk factors for recurrent UTI. The only consistently
documented behavioral risk factors for recurrent UTI
include frequent sexual intercourse and spermicide use. In
postmenopausal women, major risk factors for recurrent
UTI include a history of premenopausal UTI and anatomic
factors affecting bladder emptying, such as cystoceles,
urinary incontinence, and residual urine.
In pregnant women, ASB has clinical consequences, and
both screening for and treatment of this condition are
indicated. Specifically, ASB during pregnancy is associated
with maternal pyelonephritis, which in turn is associated
with preterm delivery. Antibiotic treatment of ASB in
pregnant women can reduce the risk of pyelonephritis,
preterm delivery, and low-birth-weight babies.
The majority of men with UTI have a functional or
anatomic abnormality of the urinary tract, most commonly
urinary obstruction secondary to prostatic hypertrophy.
That said, not all men with UTI have detectable urinary
abnormalities; this point is particularly relevant for men
≤45 years of age. Lack of circumcision is associated with
an increased risk of UTI because Escherichia coli is more
likely to colonize the glans and prepuce and subsequently
migrate into the urinary tract of uncircumcised men.
Women with diabetes have a two- to threefold higher rate
of ASB and UTI than women without diabetes; there is
insufficient evidence on which to base a corresponding
statement about men. Increased duration of diabetes and the
use of insulin rather than oral medication are associated
with an elevated risk of UTI among women with diabetes.
Poor bladder function, obstruction in urinary flow, and
incomplete voiding are additional factors commonly found
in patients with diabetes that increase the risk of UTI.
Impaired cytokine secretion may contribute to ASB in
diabetic women. The sodium–glucose co-transporter 2
(SGLT2) inhibitors used for treatment of diabetes result in
glycosuria and may be associated with small increases in
the risk of UTI.
ETIOLOGY
The uropathogens causing UTI vary by clinical syndrome
but are usually enteric gram-negative rods that have
migrated to the urinary tract. The susceptibility patterns of
these organisms vary by clinical syndrome and by
geography. In acute uncomplicated cystitis in the United
States, the etiologic agents are highly predictable: E. coli
accounts for 75–90% of isolates; Staphylococcus sapro-
phyticus for 5–15% (with particularly frequent isolation
from younger women); and Klebsiella, Proteus,
Enterococcus, and Citrobacter species, along with other
organisms, for 5–10%. Similar etiologic agents are found in
Europe and Brazil. The spectrum of agents causing
uncomplicated pyelonephritis is similar, with E. coli
predominating. In complicated UTI (e.g., CAUTI), E. coli
remains the predominant organism, but other aerobic gram-
negative rods, such as Pseudomonas aeruginosa and
Klebsiella, Proteus, Citrobacter, Acinetobacter, and
Morganella species, also are frequently isolated. Gram-
positive bacteria (e.g., enterococci and Staphylococcus
aureus) and yeasts also are important pathogens in com-
plicated UTI. Data on etiology and resistance are generally
obtained from laboratory surveys and should be understood
in the context that organisms are identified only in cases in
which urine is sent for culture—typically, when
complicated UTI or pyelonephritis is suspected. Genetic
sequencing of the bladder microbiome or of all the bacteria
that can be identified in the bladder has consistently
demonstrated that more bacterial species are present than
can be identified by routine culture methods, in both
symptomatic and asymptomatic states. The clinical
significance of these non-cultivatable organisms is
unknown but has challenged the assumption that the
bladder is normally a sterile site.
The available data demonstrate a worldwide increase in the
resistance of E. coli to antibiotics commonly used to treat
UTI. North American and European surveys from women
with acute cystitis have documented resistance rates of
>20% to trimethoprim-sulfamethoxazole (TMP-SMX) in
many regions and >10% to ciprofloxacin in some regions.
In community-acquired infections, the increased prevalence
of multidrug-resistant uropathogens has left few oral
options for therapy in some cases. Since resistance rates
vary by local geographic region, with individual patient
characteristics, and over time, it is important to use current
and local data when choosing a treatment regimen.
PATHOGENESIS
The urinary tract can be viewed as an anatomic unit linked
by a continuous column of urine extending from the urethra
to the kidneys. In the majority of UTIs, bacteria establish
infection by ascending from the urethra to the bladder.
Continuing ascent up the ureter to the kidney is the
pathway for most renal parenchymal infections. However,
introduction of bacteria into the bladder does not inevitably
lead to sustained and symptomatic infection. The interplay
of host, pathogen, and environmental factors determines
whether tissue invasion and symptomatic infection will
ensue (Fig. 130-1). For example, bacteria often enter the
bladder after sexual intercourse, but normal voiding and
innate host defense mechanisms in the bladder eliminate
these organisms. Any foreign body in the urinary tract, such
as a urinary catheter or stone, provides an inert surface for
bacterial colonization. Abnormal micturition and/or
significant residual urine volume promotes infection. In the
simplest of terms, anything that increases the likelihood of
bacteria entering the bladder and staying there increases the
risk of UTI.
Bacteria can gain access to the urinary tract through the
bloodstream. However, hematogenous spread accounts for
<2% of documented UTIs and usually results from
bacteremia caused by relatively virulent organisms, such as
Salmonella and S. aureus. Indeed, the isolation of either of
these pathogens from a patient without a catheter or other
instrumentation warrants a search for a bloodstream source.
Hematogenous infections may produce focal abscesses or
areas of pyelonephritis within a kidney and result in
positive urine cultures. The pathogenesis of candiduria is
distinct in that the hematogenous route is common. The
presence of Candida in the urine of a non-instrumented
immunocompetent patient implies either genital
contamination or potentially widespread visceral
dissemination.
Environmental Factors
VAGINAL ECOLOGY Vaginal ecology is an important
environmental factor affecting the risk of UTI in women.
Colonization of the vaginal introitus and periurethral area
with organisms from the intestinal flora (usually E. coli) is
the critical initial step in the pathogenesis of UTI. Sexual
intercourse is associated with an increased risk of vaginal
colonization with E. coli and thereby increases the risk of
UTI. Nonoxynol-9 in spermicide is toxic to the normal
vaginal lactobacilli and thus is likewise associated with an
increased risk of E. coli vaginal colonization and
bacteriuria. In postmenopausal women, the previously
predominant vaginal lactobacilli are replaced with
colonizing gram-negative bacteria. The use of topical
estrogens to prevent UTI in postmenopausal women is
controversial; given the side effects of systemic hormone
replacement, oral estrogens should not be used to prevent
UTI.
ANATOMIC AND FUNCTIONAL ABNORMALITIES
Any condition that permits urinary stasis or obstruction
predisposes the individual to UTI. Foreign bodies such as
stones or urinary catheters provide an inert surface for
bacterial colonization and formation of a persistent biofilm.
Thus, vesicoureteral reflux, ureteral obstruction secondary
to prostatic hypertrophy, neurogenic bladder, and urinary
diversion surgery create an environment favorable to UTI.
In persons with such conditions, E. coli strains lacking
typical urinary virulence factors are often the cause of
infection. Inhibition of ureteral peristalsis and decreased
ureteral tone leading to vesicoureteral reflux are important
in the pathogenesis of pyelonephritis in pregnant women.
Anatomic factors—specifically, the distance of the urethra
from the anus—are considered to be the primary reason
why UTI is predominantly an illness of young women
rather than of young men.
Host Factors
The genetic background of the host influences the
individual’s susceptibility to recurrent UTI, at least among
women. A familial disposition to UTI and to pyelonephritis
is well documented. Women with recurrent UTI are more
likely to have had their first UTI before the age of 15 years
and to have a maternal history of UTI. A component of the
underlying pathogenesis of this familial predisposition to
recurrent UTI may be persistent vaginal colonization with
E. coli, even during asymptomatic periods. Vaginal and
periurethral mucosal cells from women with recurrent UTI
bind threefold more uropathogenic bacteria than do
mucosal cells from women without recurrent infection.
Epithelial cells from women who are non-secretors of
certain blood group antigens may possess specific types of
receptors to which E. coli can bind, thereby facilitating
colonization and invasion. Mutations in host innate immune
response genes (e.g., those coding for Toll-like receptors
and the interleukin 8 receptor) also have been linked to
recurrent UTI and pyelonephritis. The genetic patterns that
predispose to cystitis and pyelonephritis appear to be
distinct.
Microbial Factors
An anatomically normal urinary tract presents a stronger
barrier to infection than a compromised urinary tract. Thus,
strains of E. coli that cause invasive symptomatic infection
of the urinary tract in otherwise normal hosts often possess
and express genetic virulence factors, including surface
adhesins that mediate binding to specific receptors on the
surface of uroepithelial cells. The best-studied adhesins are
the P fimbriae, hair-like protein structures that interact with
a specific receptor on renal epithelial cells. (The letter P
denotes the ability of these fimbriae to bind to blood group
antigen P, which contains a d-galactose-d-galactose
residue.) P fimbriae are important in the pathogenesis of
pyelonephritis and subsequent bloodstream invasion from
the kidney.
Another adhesin is the type 1 pilus (fimbria), which all E.
coli strains possess but not all E. coli strains express. Type
1 pili are thought to play a key role in initiating E. coli
bladder infection; they mediate binding to mannose on the
luminal surface of bladder uroepithelial cells. Toxins, metal
(iron) acquisition systems, biofilm formation, and capsules
can also contribute to the ability of pathogenic E. coli to
thrive in the bladder.
APPROACH TO THE PATIENT
Clinical Syndromes
The most important issue to be addressed when a UTI is
suspected is the characterization of the clinical syndrome
as ASB, uncomplicated cystitis, pyelonephritis,
prostatitis, or complicated UTI. This information will
shape the diagnostic and therapeutic approach.
ASYMPTOMATIC BACTERIURIA
A diagnosis of ASB can be considered only when the
patient does not have local or systemic symptoms
referable to the urinary tract. The clinical presentation is
usually bacteriuria detected incidentally when a patient
undergoes a screening urine culture for a reason unrelated
to the genitourinary tract. Systemic signs or symptoms
such as fever, altered mental status, and leukocytosis in
the setting of a positive urine culture are nonspecific and
do not merit a diagnosis of symptomatic UTI unless other
potential etiologies have been considered.
CYSTITIS
The typical symptoms of cystitis are dysuria, urinary
frequency, and urgency. Nocturia, hesitancy, suprapubic
discomfort, and gross
hematuria are often noted as well. Unilateral back or flank
pain is generally an indication that the upper urinary tract
is involved. Fever also is an indication of invasive
infection of either the kidney or the prostate.
PYELONEPHRITIS
Mild pyelonephritis can present as low-grade fever with
or without lower-back or costovertebral-angle pain,
whereas severe pyelonephritis can manifest as high fever,
rigors, nausea, vomiting, and flank and/or loin pain.
Symptoms are generally acute in onset, and symptoms of
cystitis may not be present. Fever is the main feature
distinguishing cystitis from pyelonephritis. The fever of
pyelonephritis typically exhibits a high spiking “picket-
fence” pattern and resolves over 72 h of therapy.
Bacteremia develops in 20–30% of cases of
pyelonephritis. Patients with diabetes may present with
obstructive uropathy associated with acute papillary
necrosis when the sloughed papillae obstruct the ureter.
Papillary necrosis may also be evident in some cases of
pyelonephritis complicated by obstruction, sickle cell
disease, analgesic nephropathy, or combinations of these
conditions. In the rare cases of bilateral papillary necrosis,
a rapid rise in the serum creatinine level may be the first
indication of the condition. Emphysematous
pyelonephritis is a particularly severe form of the disease
that is associated with the production of gas in renal and
perinephric tissues and occurs almost exclusively in
diabetic patients (Fig. 130-2). Xanthogranulomatous
pyelonephritis occurs when chronic urinary obstruction
(often by staghorn calculi), together with chronic
infection, leads to suppurative destruction of renal tissue
(Fig. 130-3). On pathologic examination, the residual
renal tissue frequently has a yellow coloration, with
infiltration by lipid-laden macrophages. Pyelonephritis
can also be complicated by intraparenchymal abscess
formation; this development should be suspected when a
patient has continued fever and/or bacteremia despite
antibacterial therapy.
PROSTATITIS
Prostatitis includes both infectious and noninfectious
abnormalities of the prostate gland. Infections can be acute
or chronic, are almost always bacterial in nature, and are far
less common than the noninfectious entity chronic pelvic
pain syndrome (formerly known as chronic prostatitis).
Acute bacterial prostatitis presents as dysuria, frequency,
and pain in the prostatic pelvic or perineal area. Fever and
chills are usually present, and symptoms of bladder outlet
obstruction are common. Chronic bacterial prostatitis
presents more insidiously as recurrent episodes of cystitis,
sometimes with associated pelvic and perineal pain. Men
who present with recurrent cystitis should be evaluated for
a prostatic focus as well as urinary retention.
COMPLICATED UTI
Complicated UTI presents as a symptomatic episode of
cystitis or pyelonephritis in a man or woman with an
anatomic predisposition to infection, with foreign body in
the urinary tract, or with factors predisposing to a delayed
response to therapy.
DIAGNOSTIC TOOLS
History
The diagnosis of any of the UTI syndromes or ASB begins
with a detailed history (Fig. 130-4). The history given by
the patient has a high predictive value in uncomplicated
cystitis. A meta-analysis evaluating the probability of acute
UTI on the basis of history and physical findings concluded
that, in women presenting with at least one symptom of
UTI (dysuria, frequency, hematuria, or back pain) and
without complicating factors, the probability of acute
cystitis or pyelonephritis is 50%. The even higher rates of
accuracy of self-diagnosis among women with recurrent
UTI probably account for the success of patient-initiated
treatment of recurrent cystitis. If vaginal discharge and
complicating factors are absent and risk factors for UTI are
present, then the probability of UTI is close to 90%, and no
laboratory evaluation is needed. A combination of dysuria
and urinary frequency in the absence of vaginal discharge
increases the probability of UTI to 96%. Further laboratory
evaluation with dipstick testing or urine culture is not
necessary in such patients before the initiation of definitive
therapy.
In applying the patient’s history as a diagnostic tool, the
physician must remember that the studies included in the
meta-analysis cited above did not enroll children,
adolescents, pregnant women, men, or patients with
complicated UTI. One significant concern is that sexually
transmitted disease—that caused by Chlamydia
trachomatis in particular— may be inappropriately treated
as UTI. This concern is particularly relevant for female
patients under the age of 25. The differential diagnosis (C.
trachomatis, Neisseria gonorrhoeae), vaginitis (Candida
albicans, Trichomonas vaginalis), herpetic urethritis,
interstitial cystitis, and noninfectious vaginal or vulvar
irritation. Women with more than one sexual partner and
inconsistent use of condoms are at high risk for both UTI
and sexually transmitted disease, and symptoms alone do
not always distinguish between these conditions.
Urine Dipstick Test, Urinalysis, and Urine Culture
Useful diagnostic tools include the urine dipstick test and
urinalysis, both of which provide point-of-care information,
and the urine culture, which can retrospectively confirm a
prior diagnosis. Understanding the parameters of the
dipstick test is important in interpreting its results. Only
members of the family Enterobacteriaceae convert nitrate to
nitrite, and enough nitrite must accumulate in the urine to
reach the threshold of detection. If a woman with acute
cystitis is forcing fluids and voiding frequently, the dipstick
test for nitrite is less likely to be positive, even when E. coli
is present. The leukocyte esterase test detects this enzyme
in polymorphonuclear leukocytes in the host’s urine,
whether the cells are intact or lysed. Many reviews have
attempted to describe the diagnostic accuracy of dipstick
testing. The bottom line for clinicians is that a urine
dipstick test can confirm the diagnosis of uncomplicated
cystitis in a patient with a reasonably high pretest prob-
ability of this disease; either nitrite or leukocyte esterase
positivity can be interpreted as a positive result. Blood in
the urine also may suggest a diagnosis of UTI. A dipstick
test negative for both nitrite and leukocyte esterase in this
type of patient should prompt consideration of other
explanations for the patient’s symptoms and collection of
urine for culture. A negative dipstick test is not sufficiently
sensitive to rule out bacteriuria in pregnant women, in
whom it is important to detect all episodes of bacteriuria.
Urine microscopy reveals pyuria in nearly all cases of
cystitis and hematuria in ~30% of cases. In current practice,
most hospital laboratories use an automated system rather
than manual examination for urine microscopy. A machine
aspirates a sample of the urine and then classifies the
particles in the urine by size, shape, contrast, light scatter,
volume, and other properties. These automated systems can
be overwhelmed by high numbers of dysmorphic red blood
cells, white blood cells, or crystals; in general, counts of
bacteria are less accurate than are counts of red and white
blood cells. The authors’ clinical recommendation is that
the patient’s symptoms and presentation should outweigh
an incongruent result on automated urinalysis.
The detection of bacteria in a urine culture is the diagnostic
gold standard for UTI; unfortunately, however, culture
results do not become available until 24 h after the patient’s
presentation. Identifying specific organism(s) can require
an additional 24 h. Studies of women with symptoms of
cystitis have found that a colony count threshold of ≥102
bacteria/mL is more sensitive (95%) and specific (85%)
than a threshold of 105/mL for the diagnosis of acute
cystitis in women. In men, the minimal level indicating
infection appears to be 103/mL. Urine specimens
frequently become contaminated with the normal microbial
flora of the distal urethra, vagina, or skin. These contami-
nants can grow to high numbers if the collected urine is
allowed to stand at room temperature. In most instances, a
culture that yields mixed bacterial species is contaminated
except in settings of long-term catheterization, chronic
urinary retention, or the presence of a fistula between the
urinary tract and the gastrointestinal or genital tract.
DIAGNOSTIC APPROACH
The approach to diagnosis is influenced by which of the
clinical UTI syndromes is suspected (Fig. 130-4).
Uncomplicated Cystitis in Women Uncomplicated cystitis
in women can be treated on the basis of history alone.
However, if the symptoms are not specific or if a reliable
history cannot be obtained, then a urine dipstick test should
be performed. A positive nitrite or leukocyte esterase result
in a woman with one symptom of UTI increases the
probability of UTI from 50% to ~80%, and empirical
treatment can be considered without further testing. In this
setting, a negative dipstick result does not rule out UTI, and
a urine culture, close clinical follow-up, and possibly a
pelvic examination are recommended. In women with
complicated UTI (e.g., due to pregnancy, suspected bac-
terial resistance, or recent UTI), a urine culture is warranted
to guide appropriate therapy.
Cystitis in Men The signs and symptoms of cystitis in men
are similar to those in women, but this disease differs in
several important ways in the male population. Collection
of urine for culture is strongly recommended when a man
has symptoms of UTI, as the documentation of bacteriuria
can differentiate the less common syndromes of acute and
chronic bacterial prostatitis from the very common entity of
chronic pelvic pain syndrome, which is not associated with
bacteriuria and thus is not usually responsive to
antibacterial therapy. Men with febrile UTI often have an
elevated serum level of prostate-specific antigen as well as
an enlarged prostate and enlarged seminal vesicles on
ultrasound— findings indicative of prostate involvement. In
a study of 85 men with febrile UTI, symptoms of urinary
retention, early recurrence of UTI, hematuria at follow-up,
and voiding difficulties were predictive of surgically
correctable disorders. Men with none of these symptoms
had normal upper and lower urinary tracts on urologic
workup. In general, men with a first febrile UTI should
have imaging performed (CT or ultrasound); if the
diagnosis is unclear or if UTI is recurrent, referral for
urologic consultation and further evaluation—including
potential localization cultures using the two- or four-glass
Meares-Stamey test (urine collection after prostate
massage)—is appropriate.
Asymptomatic Bacteriuria The diagnosis of ASB
involves both microbiologic and clinical criteria. The
microbiologic criterion (including in urinary catheter–
associated asymptomatic bacteriuria) is ≥105 bacterial
CFU/mL of urine. The clinical criterion is an absence of
signs or symptoms referable to UTI.
TREATMENT
Urinary Tract Infections
Treatment of UTI accounts for a major proportion of
antimicrobial use in ambulatory care, inpatient care, and
long-term-care settings. Responsible use of antibiotics for
this common infection has broad implications for
preserving antibiotic effectiveness into the future. That
said, antimicrobial therapy is warranted for any UTI that
is truly symptomatic. The choice of antimicrobial agent,
the dose, and the duration of therapy depend on the site of
infection and the presence or absence of complicating
conditions. Each category of UTI warrants a different
approach based on the particular clinical syndrome.
Antimicrobial resistance among uropathogens varies from
region to region and impacts the approach to empirical
treatment of UTI. E. coli ST131 is the predominant
multilocus sequence type found worldwide as the cause of
multidrug-resistant UTI. Recommendations for treatment
must be considered in the context of local resistance
patterns and national differences in some agents’
availability. For example, fosfomycin and pivmecillinam
are not available in all countries but are considered first-
line options where they are available because they retain
activity against a majority of uropathogens that produce
extended-spectrum β-lactamases. Thus, therapeutic
choices should depend on local resistance, drug
availability, and individual patient factors such as recent
travel and antimicrobial use.
UNCOMPLICATED CYSTITIS IN WOMEN
Since the species and antimicrobial susceptibilities of the
bacteria that cause acute uncomplicated cystitis are highly
predictable, many episodes of uncomplicated cystitis can be
managed over the telephone (Fig. 130-4). Most patients
with other UTI syndromes require further diagnostic
evaluation. Although the risk of serious complications with
telephone management appears to be low, studies of tele-
phone management algorithms generally have involved
otherwise healthy women who are at low risk of
complications of UTI.
In 1999, TMP-SMX was recommended as the first-line
agent for treatment of uncomplicated UTI in the
published guidelines of the Infectious Diseases Society of
America. Since then, antibiotic resistance among
uropathogens causing uncomplicated cystitis has
increased, appreciation of the importance of collateral
damage (as defined below) has increased, and newer
agents have been studied. Unfortunately, there is no
longer a single best agent for acute uncomplicated
cystitis.
Collateral damage refers to the adverse ecologic effects
of antimicrobial therapy, including killing of the normal
flora and selection of drug-resistant organisms. The
implication of collateral damage for UTI management is
that a drug that is highly efficacious for the treatment of
UTI is not necessarily the optimal first-line agent if it also
has pronounced secondary effects on the normal flora or
is likely to adversely affect resistance patterns. Drugs
used for UTI that have a minimal effect on fecal flora
include pivmecillinam, fosfomycin, and nitrofurantoin. In
contrast, trimethoprim, TMP-SMX, quinolones, and
ampicillin affect the fecal flora more significantly; these
drugs are notably the agents for which rising resistance
levels have been documented.
Choosing judiciously whether to initiate antibiotic therapy
and then selecting the most urinary-focused agent for the
shortest appropriate duration are important factors in
global efforts to stem the rise of antimicrobial-resistant
organisms. Several effective therapeutic regimens are
available for acute uncomplicated cystitis in women
(Table 130-1). Well-studied first-line agents include
TMP-SMX and nitrofurantoin. Second-line agents include
β-lactams. There is increasing experience with the use of
fosfomycin for UTIs (including complicated infections),
particularly for infections caused by multidrug-resistant
E. coli. According to an advisory from the U.S. Food and
Drug Administration (FDA), fluoroquinolones should not
be used for uncomplicated cystitis unless no alternatives
are available. Pivmecillinam is not currently available in
the United States or Canada but is a popular agent in
some European countries. The pros and cons of specific
agents are discussed briefly below.
Traditionally, TMP-SMX has been recommended as first-
line treatment for acute cystitis, and it remains appropriate
to consider the use of this drug in regions with resistance
rates not exceeding 20%. In women with recurrent UTI,
prior cultures can be used as a guide to TMP-SMX
susceptibility, although interim acquisition of resistant
bacteria can occur. TMP-SMX resistance has clinical
significance: in TMP-SMX-treated patients with resistant
isolates, the time to symptom resolution is longer and
rates of both clinical and microbiologic failure are higher.
Individual host factors associated with an elevated risk of
UTI caused by a strain of E. coli resistant to TMP-SMX
include recent use of TMP-SMX or another antimicrobial
agent and recent travel to an area with high rates of TMP-
SMX resistance. The optimal setting for empirical use of
TMP-SMX is uncomplicated UTI in a female patient who
has an established relationship with the practitioner and
who can thus seek further care if her symptoms do not
respond promptly.
Resistance to nitrofurantoin remains low despite >60
years of use, as several mutational steps are required for
the development of bacterial resistance to this drug.
Nitrofurantoin remains highly active against E. coli and
most non–E. coli isolates. Proteus, Pseudomonas,
Serratia, Enterobacter, and yeasts are all intrinsically
resistant to this drug. Although nitrofurantoin has
traditionally been prescribed as a 7-day regimen,
guidelines now recommend a 5-day course, which is as
effective as a 3-day course of TMP-SMX for treatment of
acute cystitis; 3-day courses of nitrofurantoin are not
recommended for acute cystitis. Nitrofurantoin does not
reach significant levels in tissue and cannot be used to
treat pyelonephritis.
Most fluoroquinolones are highly effective as short-
course therapy for cystitis; the exception is moxifloxacin,
which may not reach adequate urinary levels. The
fluoroquinolones commonly used for UTI include
ciprofloxacin and levofloxacin. The two main concerns
about fluoroquinolone use for acute cystitis are the
propagation of fluoroquinolone resistance, not only
among uropathogens but also among other organisms
causing more serious and difficult-to-treat infections at
other sites, and their rare but potentially serious adverse
effects. For example, quinolone use in certain
populations, including adults >60 years of age, has been
associated with an increased risk of Achilles tendon
rupture. Other potential side effects include irreversible
neuropathy. In light of these detrimental effects, the FDA
issued an advisory against using fluoroquinolones to treat
acute cystitis in patients who have other therapeutic
options.
β-Lactam agents generally have not performed as well as
TMP-SMX or fluoroquinolones in acute cystitis. Rates of
pathogen eradication are lower and relapse rates are
higher with β-lactam drugs. The generally accepted
explanation is that β-lactams fail to eradicate
uropathogens from the vaginal reservoir. Many strains of
E. coli that are resistant to TMP-SMX are also resistant to
amoxicillin and cephalexin; thus, these drugs should be
used only for patients infected with susceptible strains.
Urinary analgesics are appropriate in certain situations to
speed resolution of bladder discomfort. The urinary tract
analgesic phenazopyridine is widely used but can cause
significant nausea. Combination analgesics containing
urinary antiseptics (methenamine, methylene blue), a
urine-acidifying agent (sodium phosphate), and an
antispasmodic agent (hyoscyamine) also are available.
Interest in the responsible use of antibiotics has led to
exploration of antibiotic-sparing approaches to the
treatment of acute uncomplicated cystitis. Both placebo and
analgesics alone have proved inferior to antibiotics for
resolution of symptoms and prevention of pyelonephritis.
Delayed therapy, in which a woman receives a prescription
for antibiotics but fills it only if symptoms fail to resolve in
a day or two, has the potential advantage of avoiding
antibiotic mild case that resolves spontaneously. The
downside is that women who really do have cystitis endure
discomfort for a longer period and may meanwhile progress
to pyelonephritis. However, one certain measure for more
responsible use of antibiotics in cystitis is to treat for the
correct duration; in practice, many episodes of acute cystitis
are treated longer than is recommended by evidence-based
guidelines.
PYELONEPHRITIS
Since patients with pyelonephritis have tissue-invasive
disease, the treatment regimen chosen should have a very
high likelihood of eradicating the causative organism and
should reach therapeutic blood levels quickly. High rates
of TMP-SMX-resistant E. coli in patients with
pyelonephritis have made fluoroquinolones the first-line
therapy for acute uncomplicated pyelonephritis. Whether
the fluoroquinolones are given orally or parenterally
depends on the patient’s tolerance for oral intake. A
randomized clinical trial demonstrated that a 7-day course
of therapy with oral ciprofloxacin (500 mg twice daily,
with or without an initial IV 400-mg dose) was highly
effective for the initial management of pyelonephritis in
the outpatient setting. Oral TMP-SMX (one double-
strength tablet twice daily for 14 days) also is effective
for treatment of acute uncomplicated pyelonephritis if the
uropathogen is known to be susceptible. If the pathogen’s
susceptibility is not known and TMP-SMX is used, an
initial IV 1-g dose of ceftriaxone is recommended. Oral β-
lactam agents are less effective than the fluoroquinolones
and should be used with caution and close follow-up.
Options for parenteral therapy for uncomplicated
pyelonephritis include fluoroquinolones, an extended-
spectrum cephalosporin with or without an
aminoglycoside, or a carbapenem. Combinations of a β-
lactam and a β-lactamase inhibitor (e.g., ampicillin-
sulbactam, ticarcillin-clavulanate, piperacillin-
tazobactam) or a carbapenem (imipenem-cilastatin,
ertapenem, meropenem) can be used in patients with more
complicated histories, previous episodes of
pyelonephritis, anticipated antimicrobial resistance, or
recent urinary tract manipulations; in general, the
treatment of such patients should be guided by urine
culture results. Once the patient has responded clinically,
oral therapy should be substituted for parenteral therapy.
UTI IN PREGNANT WOMEN
Nitrofurantoin, ampicillin, and the cephalosporins are
considered relatively safe in early pregnancy. One
retrospective case-control study suggesting an association
between nitrofurantoin and birth defects has not been
confirmed. Sulfonamides should clearly be avoided both
in the first trimester (because of possible teratogenic
effects) and near term (because of a possible role in the
development of kernicterus). Fluoroquinolones are
avoided because of possible adverse effects on fetal
cartilage development. Ampicillin and the cephalosporins
have been used extensively in pregnancy and are the
drugs of choice for the treatment of asymptomatic or
symptomatic UTI in this group of patients. Generally,
pregnant women with ASB are treated for 4–7 days in the
absence of evidence to support single-dose therapy. For
pregnant women with overt pyelonephritis, parenteral β-
lactam therapy with or without aminoglycosides is the
standard of care.
UTI IN MEN
Since the prostate is involved in the majority of cases of
febrile UTI in men, the goal in these patients is to eradicate
the prostatic infection as well as the bladder infection. A 7-
to 14-day course of a fluoroquinolone or TMP-SMX is
recommended if the uropathogen is susceptible. If acute
bacterial prostatitis is suspected, antimicrobial therapy
should be initiated after urine and blood are obtained for
cultures. Therapy can be tailored to urine culture results
and should be continued for 2–4 weeks. For documented
chronic bacterial prostatitis, a 4- to 6-week course of
antibiotics is often necessary. Recurrences, which are not
uncommon in chronic prostatitis, often warrant a 12-week
course of treatment.
COMPLICATED UTI
Complicated UTI (other than that discussed above) occurs
in a heterogeneous group of patients with a wide variety
of structural and functional abnormalities of the urinary
tract and kidneys. The range of species and their
susceptibility to antimicrobial agents are likewise
heterogeneous. As a consequence, therapy for
complicated UTI must be individualized and guided by
urine culture results. Frequently, a patient with
complicated UTI will have prior urine-culture data that
can be used to guide empirical therapy while current
culture results are pending. Xanthogranulomatous
pyelonephritis is treated with nephrectomy. Percutaneous
drainage can be used as the initial therapy in
emphysematous pyelonephritis and can be followed by
elective nephrectomy as needed. Papillary necrosis with
obstruction requires intervention to relieve the obstruction
and to preserve renal function.
ASYMPTOMATIC BACTERIURIA
Treatment of ASB does not decrease the frequency of
symptomatic infections or complications except in
pregnant women, persons undergoing urologic surgery,
and perhaps neutropenic patients and renal transplant
recipients. Treatment of ASB in pregnant women and
patients undergoing urologic procedures should be
directed by urine culture results. In all other populations,
screening for and treatment of ASB are discouraged. The
majority of cases of catheter-associated bacteriuria are
asymptomatic and do not warrant antimicrobial therapy.
CATHETER-ASSOCIATED UTI
Multiple institutions have released guidelines for the
treatment of CAUTI, which is defined by bacteriuria and
symptoms in a catheterized patient. The signs and
symptoms either are localized to the urinary tract or can
include otherwise unexplained systemic manifestations,
such as fever. The accepted threshold for bacteriuria to
meet the definition of CAUTI is ≥103 CFU/mL of urine,
while the threshold for bacteriuria to meet the definition
of ASB is ≥105 CFU/mL.
As catheters provide a conduit for bacteria to enter the
bladder, bacteriuria is inevitable with long-term catheter
use. The typical signs and symptoms of UTI, including
pain, urgency, dysuria, fever, peripheral leukocytosis, and
pyuria, have less predictive value for the diagnosis of
infection in catheterized patients. Furthermore, the
presence of bacteria in the urine of a patient who is febrile
and catheterized does not necessarily mean that the
patient has CAUTI, and other explanations for the fever
should be considered.
The etiology of CAUTI is diverse, and urine culture
results are essential to guide treatment. Fairly good
evidence supports the practice of catheter change during
treatment for CAUTI. The goal is to remove biofilm-
associated organisms that could serve as a nidus for
reinfection. Pathology studies reveal that many patients
with long-term catheters have occult pyelonephritis. A
randomized trial in persons with spinal cord injury who
were undergoing intermittent catheterization found that
relapse was more common after 3 days of therapy than
after 14 days. In general, a 7- to 14-day course of anti-
biotics is recommended, but further studies on the optimal
duration of therapy are needed.
The best strategy for prevention of CAUTI is to avoid
insertion of unnecessary catheters and to remove catheters
once they are no longer necessary. Quality-improvement
collaboratives that have addressed technical aspects of
CAUTI prevention (such as avoidance of inappropriate
catheterization) as well as team communication strategies
have shown the benefit of this approach in decreasing
CAUTI in both acute- and long-term-care settings.
Antimicrobial catheters impregnated with silver or
nitrofurazone have not been shown to provide significant
clinical benefit in terms of reducing rates of symptomatic
UTI. Evidence is insufficient to recommend suprapubic
catheters and condom catheters as alternatives to indwelling
urinary catheters as a means to prevent bacteriuria.
However, intermittent catheterization may be preferable to
long-term indwelling urethral catheterization in certain
populations (e.g., spinal cord–injured persons) to prevent
both infectious and anatomic complications.
CANDIDURIA
The appearance of Candida in the urine is an increasingly
common complication of indwelling catheterization,
particularly for patients in the intensive care unit, those
taking broad-spectrum antimicrobial drugs, and those with
underlying diabetes mellitus. In many studies, >50% of
urinary Candida isolates have been found to be non-
albicans species. The clinical presentation varies from a
laboratory finding without symptoms to pyelonephritis and
even sepsis. Removal of the urethral catheter results in
resolution of candiduria in more than one-third of
asymptomatic cases. Treatment of asymptomatic patients
does not appear to decrease the frequency of recurrence of
candiduria. Therapy is recommended for patients who have
symptomatic cystitis or pyelonephritis and for those who
are at high risk for disseminated disease. High-risk patients
include those with neutropenia, those who are undergoing
urologic manipulation, those who are clinically unstable,
and low-birth-weight infants. Fluconazole (200–400 mg/d
for 7–14 days) reaches high levels in urine and is the first-
line regimen for Candida infections of the urinary tract.
Although instances of successful eradication of candiduria
by some of the newer azoles and echinocandins have been
reported, these agents are characterized by only low-level
urinary excretion and thus are not recommended. For
Candida isolates with high levels of resistance to
fluconazole, oral flucytosine and/ or parenteral
amphotericin B are options. Bladder irrigation with
amphotericin B generally is not recommended.
PREVENTION OF RECURRENT UTI IN WOMEN
Recurrence of uncomplicated cystitis in reproductive-age
women is common, and a preventive strategy is indicated if
recurrent UTIs are interfering with a patient’s lifestyle. The
threshold of two or more symptomatic episodes per year is
not absolute; decisions about interventions should take the
patient’s preferences into account.
Three prophylactic strategies are available: continuous,
postcoital, and patient-initiated therapy. Continuous
prophylaxis and postcoital prophylaxis usually entail low
doses of TMP-SMX, a fluoroquinolone, or nitrofurantoin.
These regimens are all highly effective during the period of
active antibiotic intake. Typically, a prophylactic regimen
is prescribed for 6 months and then discontinued, at which
point the rate of recurrent UTI often returns to baseline. If
bothersome infections recur, the prophylactic program can
be reinstituted for a longer period. Selection of resistant
strains in the fecal flora has been documented in studies of
women taking prophylactic antibiotics for 12 months.
Patient-initiated therapy involves supplying the patient
with materials for urine culture and with a course of
antibiotics for self-medication at the first symptoms of
infection. The urine culture is refrigerated and delivered to
the physician’s office for confirmation of the diagnosis.
When an established and reliable patient–provider
relationship exists, the urine culture can be omitted as long
as the symptomatic episodes respond completely to short-
course therapy and are not followed by relapse.
Non-antimicrobial prevention is increasingly being
studied. Lactobacillus probiotics are one appealing
approach to UTI prevention, but there is a paucity of data to
support this strategy. Similarly, studies of cranberry
products for UTI prevention have produced mixed results.
Varied dosing and product composition between studies
remains an issue for providing clinical guidance.
PROGNOSIS
Cystitis is a risk factor for recurrent cystitis and
pyelonephritis. ASB is common among elderly and
catheterized patients but does not in itself increase the risk
of death. The relationships among recurrent UTI, chronic
pyelonephritis, and renal insufficiency have been widely
studied. In the absence of anatomic abnormalities such as
reflux, recurrent infection in children and adults does not
lead to chronic pyelonephritis or to renal failure. Moreover,
infection does not play a primary role
in chronic interstitial nephritis; the primary etiologic factors
in this condition are analgesic abuse, obstruction, reflux,
and toxin exposure. In the presence of underlying renal
abnormalities (particularly obstructing stones), infection as
a secondary factor can accelerate renal parenchymal
damage. In spinal cord–injured patients, use of a long-term
indwelling bladder catheter is a well-documented risk
factor for bladder cancer. Chronic bacteriuria resulting in
chronic inflammation is one possible explanation for this
observation.